Acquired immune deficiency syndrome (AIDS) is a fatal disease of newly-recognized epidemic proportions, affecting infants, children and adults. It is estimated that 30-40% of AIDS patients develop a progressive dementing encephalopathy, where the clinical severity of dysfunction contrasts with the paucity of neuropathological findings. Recent studies have shown that the probable etiologic agent of AIDS is a retrovirus, HTLV-III, which has been shown to be present in the brains of children and adults wih AIDS encephalopathy. The present research plan is designed to test the hypothesis that AIDS encephalopathy is due to a primary infection of brain by this retrovirus, using four complementary techniques. Post-mortem brain tissue will be examined both by immunocytochemical techniques to identify viral antigen and by in situ hybridization using HTLV-III specific recombinant DNA probes to identify viral nucleic acid sequences. Neuropathological examination of those brain regions and cell types which become infected will offer important clues to the viral cytopathology. Growth of HTLV-III in primary neuronal and glial cells in vitro will be studied as a guide to the neurotropism and neurovirulence of this virus. Neuroadaptation of HTLV-III to small laboratory animals such as BALB/c mice will be undertaken, in order to develop an animal model of the disease which will be essential for therapeutic trials. Finally, human fetal brain tissue will be explanted to athymic (nude) mice using a newly-developed protocol which allows normal cytodifferentiation and morphogenesis of the explanted tissue, for study of HTLV-III infection of fetal brain under controlled conditions in vivo. These studies will provide important information on therapeutic implications of persistent retrovirus infection of the human brain, and on the consequences of fetal exposure to HTLV-III.